1. Field of the Invention
The present invention is directed to certain selected conventional antimalarial compounds, and more particularly, the present invention is directed to a method for substantially increasing the bioavailability of the same so as to permit rapid therapeutically effective antimalarial blood levels of the same to be achieved.
2. Description of the Prior Art
6-8-Dichloro-.alpha.-(dibutylaminomethyl-2-(3',4'-dichlorophenyl)-4-quinoli nemethanol, 3-Dibutylamino-1-[2,6-bis(4-trifluoromethylphenyl)-4-pyridyl] propanol and 1,3-Dichloro-6-trifluoromethyl-9-[1-hydroxy-3-(dibutylamino) propyl]-phenanthrene are well known compounds somewhat useful in the treatment of malaria in warm-blooded animals, e.g., humans. For instance, see, R. E. Lutz, et al, J. Amer. Chem. Soc., 68, 1813 (1946), P. Blumbergs, et al, J. Med. Chem., 15, No. 8, 808 (1972), and W. T. Colwell, et al, J. Med. Chem., 15, No. 7, 771 (1972).
Unfortunately, because of the extremely poor solubility of these compounds therapeutically effective antimalarial blood levels of the same can only be achieved when administering the same around the clock for an extended period of time. For example, the aqueous solubility of 6,6-Dichloro-.alpha.-(dibutylaminomethyl-2-(3',4'-Dichlorophenyl)-4-quinol inemethanol is approximately 1.0 mg per liter of water whereas the solubility of 3-Dibutylamino-1-[2,6-bis(4-trifluoromethylphenyl)-4-pyridyl] propanol is approximately 7.0 mg per liter of water, respectively. As can be seen, due to this extremely poor solubility, massive doses of these compounds must be administered before any therapeutically effective blood levels of the same can be achieved.
For a number of years, numerous investigators have attempted a myriad of structural modifications to these compounds in the hope of increasing their solubility which in turn would increase the bioavailability of the same (the ability of the compound to achieve a rapid therapeutically effective antimalarial blood level). However, all attempts have met with little, if any, success. Similarly, investigators have also attempted to pharmaceutically formulate these compounds in such a manner as to increase the solubility of the same, and hence, the bioavailability thereof. However, again, little, if any, success has been observed.
Consequently, it is apparent that a great need exists for a means to formulate the above-identified compounds to the extent that (1) a rapid therapeutically effective antimalarial blood level of the same can be achieved without (2) increased toxicity.